Tetracyclines are known “broad spectrum” antibiotics and have become widely used for therapeutic purposes. Tetracyclines have been found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. The first use of tetracycline antibiotics dates as far back as 1948. Examples of pharmaceutically active tetracycline and tetracycline analogue compositions may be found in U.S. Pat. Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. Tetracyclines may also be used to treat inflammatory skin disorders, including dermatitis, psoriasis, pyoderma gangrenosum, acne and rosacea.
Acne vulgaris, also referred to as acne, is both an inflammatory skin disorder and a bacterial infection. It is a disorder resulting from hormones affecting the sebaceous glands, which leads to plugged pores and outbreaks of lesions, or pimples. Acne is the most common skin disease in the United States, affecting nearly 17 million people. Severe acne can lead to disfiguration, and permanent scarring.
Acne is described as a disorder of the pilosebaceous units (PSUs). Found over most of the body, PSUs consist of sebaceous glands, which make an oily substance that normally empties onto the skin surface through the opening of the follicle, also called a pore. When the pore is plugged, the mixture of oil and cells allows bacteria that normally live on the skin to grow in the plugged follicles, which produce chemicals and enzymes and attract white blood cells that cause inflammation. The plugged follicle breaks down, the sebum, shed skin cells and bacteria disseminate into the nearby tissues, leading to lesions or pimples.
Acne is commonly treated with systemic antibiotics, including tetracyclines, to reduce the growth of bacteria. Efficacy is thought to be due to an effect on Propionibacterium acnes (P. acnes) as well as the intrinsic anti-inflammatory properties of these antibiotics. Propionibacterium acnes is a relatively slow growing, typically aerotolerant anaerobic gram positive bacterium (rod) that is linked to acne. Tetracyclines are known to be effective in killing P. acnes and other bacteria and have been used to treat acne because of their antibacterial and anti-inflammatory properties.
Rosacea is a skin disorder characterized by facial redness, mainly affecting individuals of north western European descent. Early symptoms of rosacea include redness on the chin, nose, skin or forehead; small visible blood vessels on the face; bumps or pimples on the face; and watery and irritated eyes. Although the causes of rosacea are poorly understood, systemic antibiotics, such as tetracyclines, are commonly prescribed for the treatment of rosacea, due to both their anti-inflammatory and antibacterial properties.
After the widespread use of tetracyclines for both major and minor illnesses and diseases led to resistance to these antibiotics, substituted tetracycline compounds were developed to treat bacterial infections, inflammation, neoplasms, and other conditions. The term “tetracycline compound” includes many compounds with a similar ring structure to tetracycline. Examples of these tetracycline compounds include: chlortetracycline, doxycycline, minocycline, oxytetracycline, demeclocycline, methacycline, sancycline, chelocardin, rolitetracycline, lymecycline, apicycline; clomocycline, guamecycline, meglucycline, mepylcycline, penimepicycline, pipacycline, etamocycline, penimocycline. For example, substituted tetracycline compounds have been disclosed in WO 2008/079339 and WO 2008/079363.
One substituted tetracycline compound is (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, described in U.S. Patent Application Publication Nos. 2008/0312193 and 2010/0305072. The free base of this compound has proven unstable for use as an active pharmaceutical ingredient. In addition, while those skilled in the art have attempted to synthesize a salt of this compound previously, only amorphous salts have been produced and these amorphous salts have shown only minimal improved stability over the free base. Accordingly, there exists a need in the art for improved stability of this substituted tetracycline compound.
The present invention is directed to the novel crystalline mono hydrochloride, mono mesylate, and mono sulfate salts of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, which exhibit superior stability over the free base and previously known salts thereof. This is a significant advancement in the state of the art.